A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate

Serine is a both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical glucose-derived serine synthesis pathway, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, ratelimiting step. Genetic loss of PHGDH is toxic towards PHGDH-overexpressing breast cancer cell lines even in the presence of exogenous serine. Here, we use a quantitative high-throughput screen to identify small molecule PHGDH inhibitors. These compounds reduce the production of glucose-derived serine in cells and suppress the growth of PHGDH-dependent cancer cells in culture and in orthotopic xenograft tumors. Surprisingly, PHGDH inhibition reduced the incorporation into nucleotides of one-carbon units from glucose-derived and exogenous serine. We conclude that glycolytic serine synthesis coordinates the use of one-carbon units from endogenous and exogenous serine in nucleotide synthesis, and suggest that one-carbon unit wasting may contribute to the efficacy of PHGDH inhibitors in vitro and in vivo.Damon Runyon Cancer Research Foundation (Sally Gordon Fellowship DRG-112-12)United States. Dept. of Defense. Breast Cancer Research Program (Postdoctoral Fellowship BC120208)American Society for Radiation Oncology (Resident Seed Grant RA-2011-1)European Molecular Biology Organization (Long-Term Fellowship)National Institutes of Health (U.S.) (R03 DA034602-01A1, R01 CA129105, R01 CA103866, and R37 AI047389)United States. Department of Defense (W81XWH-14-PRCRP-IA)Alexander and Margaret Stewart Trus

Stereotypes, Discrimination, and Ethnic Identity among Asian American Emerging Adults during COVID-19

As the COVID-19 pandemic emerged, overt discrimination against Asian Americans has increased, affecting the psychological well-being of Asian American Emerging Adults (AAEAs) (Okazaki et al., 2022; Tang et al., 2023; Zhou et al., 2023). However, attention to discrimination was frequently disregarded, which may be linked to the prevalent racial stereotypes such as the model minority stereotype and the perpetual foreigner (Yip et al., 2021). While various scholarly efforts have attempted to identify the impact of COVID-19-related discrimination on Asian Americans, no study has yet investigated the complex dynamics between the long historical racial stereotypes, overt discrimination during COVID-19, and the impact on the psychological well-being of AAEAs. Accordingly, this explanatory sequential mixed-method study aims to explore the following questions: (1) What is the role of COVID-19-related discrimination as a mediator between racial stereotypes and Psychological well-being? (2) What is the role of ethnic-racial identity as a moderator in a mediation model of COVID-19-related discrimination between racial stereotypes and psychological well-being? (3) How are AAEAs making meaning of racial stereotypes, COVID-19 racial discrimination, and ERI in relation to their psychological well-being? The mixed-method study recruited 739 AAEAs (Mage = 24.47) for the survey and 20 AAEAs (Mage = 22.95) for the interviews from January 2023 through July 2023. This study utilized structural equation modeling to test the moderated mediation model and employed reflexive thematic analysis to analyze the themes of the interview narratives. The quantitative results confirmed the significant mediating role of COVID-19-related discrimination in the relationship between stereotypes and psychological well-being among AAEAs, as well as the moderating role of Ethnic Racial Identity (ERI) exploration, depend on the level of stereotypes in the mediation model. Understanding the complex relationship among variables, the qualitative interview narratives yielded themes for each research question: (1) The Relation between Stereotypes and COVID-19-related Discrimination, (2) Psychological Impact due to Racial Discrimination during the COVID-19 Pandemic, (3) Recrystallized ERI Exploration during Emerging Adulthood, (4) Racial Stereotype and ERI Exploration Development, (5) Reciprocal Relations between COVID-19 Related Discrimination and ERI Exploration Development, and (6) Enduring Discrimination after the COVID-19 Pandemic. This study discovers the mental health vulnerabilities of AAEAs against racial discrimination during the COVID-19 pandemic by incorporating racial stereotypes and ERI exploration development. The impact of COVID-19-related discrimination on psychological well-being was exacerbated or buffered by the interaction of stereotypes and ERI, particularly during emerging adulthood, when individuals often recrystallize their ERI in the face of stereotypes and racial discrimination. The study underscores the need for a close examination of the interaction between ERI and stereotypes to gain deeper insights into the psychological well-being of AAEAs against discriminatory experiences. Ultimately, this study emphasizes the importance of providing support and resources for the mental health of AAEAs as they navigate their transition into adulthood with heightened anxiety and fear of racial discrimination against Asian Americans after the pandemic

A PHGDH inhibitor reveals coordination of serine synthesis and 1-carbon unit fate

Serine is a both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical glucose-derived serine synthesis pathway, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, rate-limiting step. Genetic loss of PHGDH is toxic towards PHGDH-overexpressing breast cancer cell lines even in the presence of exogenous serine. Here, we use a quantitative high-throughput screen to identify small molecule PHGDH inhibitors. These compounds reduce the production of glucose-derived serine in cells and suppress the growth of PHGDH-dependent cancer cells in culture and in orthotopic xenograft tumors. Surprisingly, PHGDH inhibition reduced the incorporation into nucleotides of one-carbon units from glucose-derived and exogenous serine. We conclude that glycolytic serine synthesis coordinates the use of one-carbon units from endogenous and exogenous serine in nucleotide synthesis, and suggest that one-carbon unit wasting may contribute to the efficacy of PHGDH inhibitors in vitro and in vivo